MHC loci encode highly polymorphic molecules involved in the presentation of self and non-self peptides to cells of the adaptative and innate immune systems. Pig-tailed macaques (Macaca nemestrina), infected with simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV), represent one of the animal models used to study HIV pathogenesis and AIDS vaccine development. The usage of this model has been limited by the paucity of knowledge about the cellular responses and antigen presentation characteristics of Mane alleles, the MHC class I molecules of pig-tailed macaques. In this study, we analyzed the CD8+ T cell responses to the p27 SIV Gag protein in 4 SHIV infected pig-tailed macaques. We found that multiple p27 Gag domains were recognized by CD8+ T lymphocytes: twenty-two different 9-mer peptides from the SIVmac Gag protein induced IFNgamma production. Among them, five were presented by Mane-A*03. CD8+ T lymphocytes recognizing these five Mane-A*03 restricted peptides exhibited combined expression of IFN alpha and TNF alpha in ex vivo assays, suggesting that they might possess antiviral activities in vivo. Moreover, CD8+ T cell responses against Mane-A*03 restricted peptides dominate all of the tested responses against SIV Gag. Based on peptide biochemical similarities, we propose that Mane-A*03 preferentially selects peptides bearing an acidic amino acid in position 2 and a hydrophobic residue at its carboxyl terminus. This report constitutes the first description of peptide binding motif for pig-tailed macaque MHC class I molecules. Neutralization resistant variants arise during the course of lentivirus infections. Rhesus monkeys, immunized using a recombinant vaccinia prime/inactivated HIV plus SIV boost regimen and challenged with a highly pathogenic SIV/HIV chimeric virus (SHIV), promptly controlled their plasma viremia. Viruses recovered from 3 of 4 of protected macaques carried common and animal-specific changes in gp120 envelope coding sequences, rendering them resistant to neutralization with antibody collected following the resolution of the acute infection. The common envelope alterations consisted of insertions and deletion of blocks of 5 to 6 amino acids within the V1 and V4 regions of gp120. The contributions of duplications/deletions to neutralization escape has been evaluated by monitoring the neutralization sensitivity of SHIV variants bearing varying numbers and combinations of repeat units in the variable domains of gp120.